The recently defined extracellular matrix protein tenascin is prominently expressed in embyrogenesis, tumor invasion and wound healing but markedly restricted in adult tissues. Tenascin is particularly prominent at epithelial-mesenchymal interfaces including skin and is markedly induced under condiitons of proliferation, repair and tumor invasion. The long term objective of this proposal is to define the role of tenascin in modulating cell-matrix interactions. The proposed studies will examine the role of tenascin in the normal homeostasis of skin and should add to our understanding of the role of the extracellular matrix in epithelial differentiation, tissue repair and tumor invasion. The specific aims include: [1] To determine the mechanism of tenascin inhibition of cell proliferation. Because this inhibition contrasts sharply with the increased tenascin found in proliferative states, comparison with cells growing in a more native matrix environment will also be undertaken. We will also examine the effects of tenascin on epidermal proliferation in vivo Tenascin knockout mice will be compared with wild type mice for the onset, quality and duration of epidermal response to known stimuli of proliferation. [2] To determine the mechanism of tenascin modulation of cell adhesion by examining effects of tenascin on adhesion induced tyrosine phosphorylation and activation of second messenger pathways including protein kinase C. [3] To determine the tenascin domains that mediate tenascin modulation of keratinocyte migration. To use transfection to alter cell production of tenascin to monitor the role of endogenous tenascin in cell migration. [4] To determine the role of tenascin in epidermal stratification and differentiation by examining the effects of exogenously added and endogenously produced tenascin on differentiation in organotypic cultures. These studies should help define the role of tenascin in cell-matrix signaling. By contributing to our understanding of the pathogenic mechanisms in diseases characterized by increased tenascin expression, this could lead to therapeutic uses of tenascin expression, this could lead to therapeutic uses of tenascin, tenascin peptides or domain specific blocking antibodies in the treatment of chronic wounds, inflammatory arthritis and cancer.